MXPA96004553A - Compositions of dosing ranitidine b - Google Patents

Abstract

The present invention relates to low dosage formulations containing ranitidine Histamine H2 receptor antagonist and its use in the treatment of gastric disorders such as episodic acidity.

Description

COMPOSITIONS OF LOW DOSING RANITIDINE -COMPO OF THE INVENTION The present invention relates to low dosage formulations containing ranitidine histamine H- receptor antagonist and to its use in the treatment of gastric disorders such as episodic acidity.

BACKGROUND OF THE INVENTION Ranitidine, N- [2- [[[5- (dimethylamino) methyl-2-furanyl] methyl] thio] ethyl] -N '-methyl-2-nitro-1,1-enetiamine, and its physiologically acceptable salts are described and claimed in British Patent Specification No. 1565966, and a particular crystalline form of ranitidine hydrochloride are described and claimed in British Patent Specification No. 2084580. In both specifications reference is made to formulations for oral administration, which they can take the form of, for example, tablets, capsules, granules, powders, solutions, syrups, suspensions, or tablets or lozenges for buccal administration. Oral administration constitutes a preferred route to administer REF: 23148 ranitidine U.S. Patent No. 5,229,137 discloses the use of a combination of ranitidine and an antacid for the treatment of episodic acidity. According to US Patent 5229137, when H- antagonists such as ranitidine are administered alone, relief of episodic acidity is not experienced until after some time after the medicine is ingested. Specifically, when 150 mg of ranitidine were administered to two patients suffering from episodic acidity, relief was obtained 45 and 60 minutes after ingestion. Therefore, according to US Patent 5229137, an antacid needs to be administered with the H_ antagonist to obtain rapid relief. When the H_ antagonist is ranitidine, the doses used in the combination are between 100 and 150 mg. Compositions containing reduced doses of H- antagonists are described in EP0193400 and W093 / 12779. European Patent EP0193400 describes a combination of an H_ antagonist, such as ranitidine, and sodium polyacrylate for use in the treatment of gastritis or gastroduodenal ulcers. In accordance with European Patent EP0193400, the synergistic effect between the H2 antagonist and the polyacrylate allow the possibility that lower or lower doses of the H_ antagonist are used. Patent application W093 / 12779 discloses the use of a combination of an anatagonist of H_, which includes ranitidine, and an antacid in the treatment of gastric disorders, wherein the combination is stabilized or buffered to confer a substantial pH equal to that of the pKa of the H_ antagonist and wherein the dose of the H_ antagonist by the unit dosage form is less than 25 mg. The lower or lower dose is said to be effective since the combination of active agents increases the availability of the H_ antagonist at the site of the receptor of the local stomach wall. European Patent Application EP0492247 also describes a composition having a reduced dose of H2 antagonist for the treatment of acidity, etc. Here the composition uses a combination of water-soluble H2 antagonist and an effervescent delivery or distribution system, such as an alkali metal bicarbonate and citric acid. The use of the effervescent distribution system is said to decrease the time to initiate the action of the H2 antagonist and increase its potency so that the formulation requires approximately twenty-five. percent of the dosage of the H antagonist commonly prescribed for the treatment of active ulcer in the duodenum. In the case of ranitidine, the effervescent delivery or delivery system reduces the dosage from 150 mg to less than approximately 37.5 mg. Dosage levels between 50 and 600 mg, such as 150 and 300 mg, of ranitidine, when administered alone are conventionally observed as conferring therapeutic benefit. In a surprising way, it has now been found that very low doses of ranitidine, administered alone, are effective in the treatment of minor gastrointestinal disorders associated with excess acid secretion, such as apisodic acidity for example, and which alleviates symptoms occurring within 30 days. -45 minutes after ingestion. The duration of the acid secretion control is also advantageous with the dosage of the invention.

DESCRIPTION OF THE INVENTION Thus, the present invention provides an oral pharmaceutical composition, such as a tablet, comprising ranitidine, or a salt thereof, Physiologically acceptable as the active ingredient alone, characterized in that the dose of ranitidine for the unit dosage form is between 10 and 30 mg, such as 25 mg, expressed as the free base weight. According to a further aspect, the present invention provides a chewable tablet comprising ranitidine, or a salt thereof, physiologically acceptable as the active ingredient alone, characterized in that the dose of ranitidine per unit dosage form is between 10 and 10. and 30 mg, such as 25 mg, expressed * as the weight should be liore. According to a further aspect, the present invention provides a method for the treatment of minor gastrointestinal disorders associated with the secretion of excess acids, which comprises administering to a patient in need of treatment, an oral pharmaceutical composition, which consists essentially of ranitidine, or a salt thereof, acceptable physio logically as the active ingredient alone, characterized in that the dose of ranitidine by the dosage form is between 10 and 30 mg, such as 25 mg, expressed as " free base weight It is to be understood that the compositions according to the invention are substantially free of antacids, a polyacrylate or an effervescent delivery or distribution system. Ranitidine can be used in tablets according to the invention in the form also of free base or a physiologically acceptable salt. The salts include salts with inorganic or organic acids, such salts as the hydrochloride, hydrobromide, sulfate, acetate, maleate, succinate, citrate, tartrate, fumarate and ascorbate. A particularly preferred ranitidine salt is the hydrochloride. Ranitidine can be used in tablets according to the invention, in the conventional form or coated or encapsulated forms of ranitidine can be used. Suitable coated or encapsulated forms are described, for example, in Patent Applications EP538034, EP523847, 092/21328, EP473431, EP459695, EP349103, CA2068366 and US5084278. The ranitidine resin adsorbates, as described in Patent Application UK2218333, can also be incorporated into tablets in accordance with the present invention. Preferably, ranitidine and its salts are used in the conventional manner. The amount of ranitidine, preferably in the form of a physiologically acceptable salt, particularly ranitidine hydrochloride, in the composition according to the invention, is preferred in the range of 10 to 30 mg, per dosage unit (eg per tablet), eg, 25 mg, expressed as the weight of free base . The unit dose (for example contained in a tablet according to the invention), can be administered up to, for example, 12 times a day, depending on the nature and severity of the conditions treated, and the age and weight of the patient. So, for example, in trafficking of minor gastrointestinal disorders, associated with excess acid secretion such as, for example, in acid management, excessive consumption of food or drink (eg, alcoholic beverages), heartburn, stomach irritation, water belching, regurgitation, cardialgia or acidity, nocturnal acidity and food-induced acidity, gastritis and dyspepsia, a dose of 25 mg, expressed as the weight of free base, can be administered up to 12 times a day, for example 6 times a day as and when want. The pharmaceutical compositions according to the invention may also contain other conventional excipients for the art such as fillers, binders, disintegrants, lubricants and desiccants. Suitable excipients are well known for those skilled in the art. Suitable binders include methyl cellulose, sodium carboxymethylcellulose, hydroxypropyl methylcellulose, alginic acid, ethylcellulose, acacia, gelatin, pregelatinized starch, sucrose syrup, polyvinylpyrrolidone, (povidone) and gum arabic. Suitable lubricants include magnesium stearate, zinc stearate, calcium stearate, stearic acid, sodium stearyl fumarate, hydrogenated vegetable oils, glyceryl palmito stearate, glyceryl behenate, sodium benzoate, sodium lauryl sulfate, magnesium lauryl sulfate, mineral oil , talc and mixtures thereof. Magnesium stearate is a preferred lubricant. Suitable desiccants include silica gel. Suitable fillers include microcrystalline cellulose. Suitable disintegrants include croscarmellose sodium. Suitable chewable tablets are described in the co-pending PTC application No. PCT / EP93 / 02763. The chewable tablets specifically disclosed in this co-pending application are not included within the scope of the present invention. Such chewable tablets comprise ranitidine, or a salt thereof, physiologically acceptable, a chewable base selected from sucrose, glucose, lactose, maltose, or a mixture thereof, a flavoring and, optionally, a strong sweetener. The chewable tablets can be prepared using the conventional steps of mixing, granulating, drying, blending, compressing and packaging. The nuclei of suitable ingestible tablets can be prepared in a conventional manner, for example, in a similar manner as described in British Patent Specification No. 2084580 which is incorporated herein by reference. Thus, for example, the required amounts of ranitidine or its salts, a lubricant, such as magnesium stearate, and optionally a pharmaceutically acceptable disintegrant, such as croscarmellose sodium, are mixed and compressed within the tablet cores. The ingestible tablets are conventionally coated with a film, according to the methods of the invention, either by organic or aqueous techniques. A preferred coating film is described in British Patent Specification No. 2218336 which is incorporated herein by reference. The following are illustrations of non-limiting examples of the pharmaceutical compositions according to the invention. Opaspray white K-1 -7000 is a suspension of titanium dioxide and hydroxypropyl cellulose in industrial methylated nuclei. Opadry Yelow Y S-1 -12606 is a mixture of hydroxypropyl 2910 methylcellulose, titanium dioxide, triacetin and yellow iron oxide. Both Opaspray and Oprady are the treaty names of Colorcon Inc., West Point, Philadelphia, USA.

REFERENCE EXAMPLE 1 MASTICABLE TABLET INGREDIENT mg / ranitidine HC1 tablet 28.0 Sucrose 2268.0 Aspartame 37.5 Povidone 50.0 Peppermint flavor 41.5 Silica gel 50.0 Magnesium stearate 25.0 Isopropyl alcohol + q.s. + does not appear in the final product EXAMPLE 2 INGERABLE TABLET CENTER OF THE TABLET mg / tablet HC1 of ranitidine 28.0 Cellulose microcrystalline 263.75 Sodium of croscarmellose type A 6.00 Magnesium stearate 2.25 Compression weight of the objective 300 mg Film Coating% p / p Unit Quantity (mg / tablet) * Methyl Hydroxypropyl 4.0 Cellulose 11.3 Opaspray White K-1-7000 3.3 4.7 Isopropyl Alcohol ** 26.3 c.s. Dichloroethane ** 66.4 c.s.

* The amount of film coating applied per tablet may be less than that established depending on the efficiency of the processes.

** It does not appear in the final product. 1'2 EXAMPLE 3 INGERABLE TABLETS TABLET NUCLEUS UNIT QUANTITIES (mg / tablet) Ranitidine HC1 28,000 Microcrystalline Cellulose 120,875 Magnesium Stearate 1,125 Total compression weight 150.00 MOVIE COATING Opadry Yelow YS-1 -12606 Purified water ** ** Withdrawal during the procedure Clinical studies In controlled studies of double-bound placebo to evaluate the efficacy of ranitidine 25 mg (administered as the hydrochloride), in the treatment of episodic acidity in the general population, both, the chewable tablets of Example 1, and the ingestible tablets of the Example 2, were effective within 30-45 minutes of administration.

It is noted that in relation to this date, the best method known by the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention. Having described the invention as above, the content of the following is claimed as property

Claims (7)

1. An oral pharmaceutical composition, comprising ranitidine, or a salt thereof, physiologically acceptable, as the active ingredient alone, characterized in that the dose of ranitidine by the unit dosage form is between 10 and 30 mg, expressed as the free base weight.

2. An oral pharmaceutical composition according to claim 1, characterized in that the dose of ranitidine per unit dosage is 25 rpg, expressed as the weight of free base.

3. An oral pharmaceutical composition, according to claim 1 or claim 2, characterized in that ranitidine is in the form of its hydrochloride salt.

4. An oral pharmaceutical composition according to any of claims 1 to 3, characterized in that the form of a tablet.

5. An oral pharmaceutical composition, according to claim 4, characterized in that it is in the form of a chewable tablet.

6. A method of treating minor gastrointestinal disorders associated with excess acid secretion, characterized in that "comprises administering to a patient in need of treatment, a composition oral pharmaceutical composition according to any one of claims 1 to 5.

7. The use of an oral pharmaceutical composition according to any of claims 1 to 5, in the manufacture of a medicament for the treatment of minor, associated gastrointestinal disorders. with the secretion of excess acids.